The present invention relates to a series of new piperidyloxyisoxazole and quinuclidinyloxyisoxazole derivatives which are useful for the treatment and prophylaxis of various disorders, notably senile dementia (including Alzheimer's disease). The invention also provides methods and compositions using these compounds as well as processes for preparing them.
In recent years, the number of elderly in the population has substantially increased, and there has been a corresponding increase in the number of age-related diseases and disorders, most notably senile dementia, including Alzheimer's disease. Senile dementia is a serious and growing problem in the world today, which can cause much discomfort and distress not only to the sufferer but also to relatives and to those responsible for them, and much research effort has been directed to attempts to cure or alleviate the condition. In particular Alzheimer's disease, in which senile dementia appears to afflict the patient prematurely, is a cause of much distress. Since the causes of senile dementia and Alzheimer's disease are presently unknown, treatment is difficult to develop and generally has to be confined merely to the relief of symptoms.
It is known that a characteristic exhibited by patients suffering from senile dementia is a decrease in the cerebral microcirculation and a reduction in cerebral metabolism, which together lead to dysfunction of cognition. Also, the early stages of senile dementia are generally accompanied by depression, and the relief of that depression would lead to an improvement in the quality of life of the sufferer.
Acetylcholine is a chemical transmitter having a wide range of activities in the body, and interference with its production and/or activity has been shown to result in a number of disorders. It has been found in patients suffering from senile dementia, including Alzheimer's disease, that the biosynthesis of acetylcholine in the brain is defective; however, even in such patients, receptors for acetylcholine in the brain may be much less affected, and they may still be functioning satisfactorily. The receptors for acetylcholine located on the pre-synaptic terminals in the brain are M.sub.2 receptors, while those located on the post-synaptic membranes in the brain are M.sub.1 and M.sub.3 receptors. The M.sub.2 receptors are abundant on the pre- and post-synapses of the heart, whilst many M.sub.1 receptors are located in the cerebral cortex and hippocampus of the brain, which play an important role in memory and cognition. Accordingly, if the M.sub.1 receptors could be stimulated during the early stages of the development of the dementia, it would be possible to alleviate the symptoms of the dementia and possibly prevent further decline. On the other hand, it is more desirable that any agent developed to stimulate the M.sub.1 receptors should not correspondingly stimulate the M.sub.2 receptors, since M.sub.2 receptors inhibit the release of acetylcholine, and that they should minimise side-effects caused by stimulation of the heart.
We have now discovered a series of new piperidyloxyisoxazole and quinuclidinyloxyisoxazole derivatives which have been found to bind selectively to M.sub.1 receptors, while binding to a much lesser extent to M.sub.2 receptors and which, therefore, as explained above, are of value for the treatment and prophylaxis of senile dementia, including Alzheimer's disease.
Surprisingly, we have found that the compounds of the present invention also bind to 5-HT.sub.3 receptors and thus interfere with 5-HT.sub.3 activity. Since it is known that 5-HT.sub.3 antagonists have anti-anxiety, anti-depressant and anti-psychotic activities, the compounds of the present invention are also expected to be of value more widely in the treatment of patients having anxiety, depression and psychosis.
A number of isoxazole derivatives have previously been described by the present inventors and co-workers for use in the treatment and prophylaxis of a variety of diseases and disorders, including cerebrovascular disorders, as centrally acting muscle relaxants and as anti-depressants. These are disclosed, for example, in copending U.S. patent application Ser. No. 07/620 843, now abandoned filed 30th Nov. 1990, U.S. patent application Ser. No. 07/537 517, filed 13th Jun. 1990, now U.S. Pat. No. 5,116,839 and U.S. patent application Ser. No. 07/585 828, filed 20th Sep. 1990, now abandoned. Of these, the closest compounds structurally are disclosed in U.S. patent application Ser. No. 07/620 843, in which there are disclosed, inter alia, compounds of formula: ##STR2## in which the symbols R each represent various groups and atoms and the symbols R' can represent various organic groups or, together with the nitrogen atom to which they are attached, can represent a heterocyclic group, including a piperidyl group. These prior art compounds differ from those of the present invention in that the piperidyl group represented by --NR'R' is necessarily attached to the remainder of the molecule via the nitrogen atom and, most importantly, by the presence in the prior art compounds of a group of formula: ##STR3## which has hitherto been considered essential to the desired activity, and which is totally absent in the compounds of the present invention.